FDA Inspections at API Manufacturers - current Warning Letter Trends
FDA对原料药生产商的检查---当前警告信趋势
Taking a look at the Warning Letters the FDA issued after inspections of activesubstance manufacturers in the 2015 fiscal year, which ended on 30 September 2015, it is first of all striking that only non-American companies are among the addressees. Almost half of them are Indian companies. Overall the numbers look like this: India (3 WLs); China (2 WLs); Canada (1 WL); Thailand (1 WL); Czech Republic (1 WL).
看一看2015财年（截止015年9月30日）FDA在对原料药生产商进行检查后签发的警告信，首先引人注意的是只有非美国公司收到警告信，而其中有一半是印度公司。总体情况如下：印度3封，中国2封，加拿大1封，泰国1封，捷克1封。
The top issue in the Warning Letters is the non-GMP compliant handling of electronic data or missing data integrity. Each of the 8 warning letters contains the following comment in the same wording:
警告信中排第一位的问题是电子数据处理不符合GMP要求，或缺乏数据完整性。8封警告信中每一封均有如下相同措词：
"Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data."
“未能防止未经授权的进入或更改数据，未能提供充分的控制来防止数据缺失”。
The lack of access control on electronic (raw) data is an issue the FDA investigators have been observing for a long time, especially during inspections in pharmaceutical companies. In this as well as in the last fiscal year there were significant deficiencies in several companies - medicinal product as well as API manufacturers - as the comments in the appropriate Warning Letters show. For more information also see the GMP news Another FDA Warning Letter with Focus on "Data Integrity" and FDA Warning Letter on Data Integrity.
对电子数据进入缺乏控制是FDA检查官很长时间来均会发现的问题，尤其是在对制药公司进行检查时。与前一财年一样，在几个公司中均有明显的缺陷----制剂和原料药生产商都一样----均在警告信中写有相同的问题。更多信息参见GMP新闻“又一封关于数据完整性的警告信”以及“FDA关于数据完整性的警告信”。
Ultimately these deficiencies can be traced back to a failure of the quality assurance unit which also affects other areas. In the Warning Letters, the following examples can be found for this:
这些缺陷最后都可以追溯到质量保证部门的失败，同时也对其它领域产生影响。在警告信中，可以发现以下例子：
"Failure of your quality unit to ensure that materials are appropriately tested and the results are reported."
“你们的质量部门未能确保原料药经过适当的检测并报告结果”。
"Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity."
“你们质量部门未能履行其职责以确保你工厂所生产的原料药符合CGMP的要求，符合既定的质量和纯度标准”。
Data were manipulated by laboratory staff (change of the file name), to fake results from identity tests in batches which in reality were not performed. Quality assurance was not able to uncover this manipulation.
化验室员工伪造数据（更改文件名称），伪造鉴别测试的结果，而实际并没有实施这些检测。质量保证部门未能发现这些伪造行为。
Despite an unknown peak in the examination for residual solvents the relevant batches were released. Upon receipt of a complaint regarding this peak an examination was conducted with the result that the contamination originated in the production process itself. Preventive control measures to avoid this contamination were not established.
虽然在一些批次的残留溶剂测试中发现有未知峰，这些批次仍被放行。在收到客户关于此峰的投诉后，对结果进行检查发现污染来源于生产工艺本身。没有采取预防控制措施来避免该污染。
"Failure to adequately investigate complaints and extend the investigations to other batches that may have been affected."
“没有对客诉进行充分的调查，没有将调查延伸至其它可能受影响的批次”。
As a result of a complaint (bad smell), a cause study was initiated which was completed prior to implementation of the preventive measures again. The CAPA measures subsequently carried out were obviously not associated with the reason for the complaint.
作为客诉（不良气味）的结果，启动了原因调查，之后实施了预防措施。随后实施的CAPA措施与客诉的原因显然并不相关。
"Failure to have appropriate controls for issuance of batch records".
“对批记录发放没有适当的控制”。
The use of document templates for batch records is out of control. These can be printed out from the production staff's personal computers. Although there is an SOP for the control of batch records there are no appropriate training records.
批记录文件模板的使用不受控。它们可以由生产员工由个人电脑直接打印出来。尽管有一个批记录控制的SOP，但并没有适当的培训记录。
"Failure to have appropriate documentation and record controls."
“没有适当的文件记录控制”。
Data for tracing raw materials are not available. Log entries are without date/visa and partly corrected with Tippex. There is an SOP prohibiting the use of correction fluid, however this was not trained.
无法追溯到原料的数据。登记本上填写的内容没有日期/签发，使用涂改液进行了部分修改。有一个SOP禁止使用修正液，但并没有进行培训。
"Failure to record activities at the time they are performed and destruction of original records."
“在活动进行及记录销毁时没有即时记录”。
Original records of critical process data on uncontrolled memos were transferred subsequently in new report templates (after batch approvals) and then destroyed.
非受控备忘录中关键工艺数据的原始记录被转抄至新的报告模板中（在批批准之后），然后被销毁。
This selection of examples shows the lack of fundamental GMP principles which leads to a blatant misconduct of staff and ultimately to quality defects in the final product. The main responsibility usually has the quality unit, which task it actually would be to ensure a thorough training in production and quality control and to monitor compliance with the appropriate regulations. These examples of non-GMP-compliant behavior are not limited to active ingredient manufacturers; there are very similar findings in Warning Letters issued to medicinal product manufacturers. An analysis of these Warning Letters issued in the fiscal year 2015 will be part of one the coming newsletters.
这些例子显示缺乏基本的GMP原则，导致员工公然违规操作，最终形成了产品质量缺陷。主要职责通常有质量部门，其任务是确保对生产和质量控制进行全面的培训，监管符合适当的法规要求。这些违反GMP行为的例子不仅限于原料药生产商，在签发给制剂和平商的警告信中也有类似的缺陷。对这些2015财年签发的警告信的分析将是下一个新闻快递的一部分。